CN1980643A - Method for the production of an abuse-proof, solid form of administration - Google Patents

Method for the production of an abuse-proof, solid form of administration Download PDF

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Publication number
CN1980643A
CN1980643A CNA2005800205443A CN200580020544A CN1980643A CN 1980643 A CN1980643 A CN 1980643A CN A2005800205443 A CNA2005800205443 A CN A2005800205443A CN 200580020544 A CN200580020544 A CN 200580020544A CN 1980643 A CN1980643 A CN 1980643A
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dosage form
preferred
mixture
active component
abuse
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CN1980643B (en
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E·阿克诺
J·巴索洛毛斯
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority claimed from PCT/EP2005/004225 external-priority patent/WO2005102286A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C43/00—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor
    • B29C43/003—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor characterised by the choice of material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C43/00—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor
    • B29C43/006—Pressing and sintering powders, granules or fibres
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    • A61J2200/20—Extrusion means, e.g. for producing pharmaceutical forms
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    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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Abstract

The present invention relates to a process for the production of an abuse-proofed solid dosage form containing at least one active ingredient with potential for abuse and a binder with a breaking strength of >=500 N, by exposing a mixture comprising the active ingredient and the binder to ultrasound and force.

Description

Preparation prevents the method for the solid dosage forms abused
The present invention relates to prepare the method that prevents the solid dosage forms abused, this dosage form comprises at least a active substance that may be abused and at least a fracture strength binding agent more than or equal to 500N, described method comprise the mixture that will comprise active substance and binding agent be exposed to ultrasonic and power under.
Many pharmaceutically active substances except the excellent activity that in their suitable purposes, has, also have abused may, promptly they can be used by the misuser and produce unexpected effect.For example, have very strong active opiate, often be used to produce anesthesia or glad state by the misuser to resisting very violent pain.
In order to make abuse become possibility, the misuser can pulverize and for example grind corresponding dosage forms in mortar, as tablet or capsule, with preferred aqueous liquid active component is extracted from the powder that obtains, and after the solution that obtains randomly filtered by velveteen or cellulose wadding, from parenteral, intravenous administration particularly.Compare with the oral administration of abuse, another phenomenon of this administering mode is the raising of further having accelerated the active component level, gives the needed effect of misuser, i.e. " kick " or " impact ".If this powder medicine nose administration promptly sucks, also can obtain this kick.Also can make the misuser produce needed kick even contain the dosage form of the active component of abuse potential in a large number by oral abuse.In order to be abused, this dosage form also can be pulverized and be extracted.
The US-A-4070494 suggestion increases a kind of expandable reagent to prevent abuse in dosage form.When adding entry and extract active component, this reagent just expands and the filtrate of guaranteeing to separate from gel is only contained a spot of active component.
Disclosed multilayer tablet is based on and prevents parenteral abuse similar methods in WO 95/20947, and described tablet contains active component and at least a gel former that might abuse respectively in different layers.
WO 03/015531 A2 discloses the another kind of method that prevents the parenteral abuse.Its described contain opioid analgesic with as the dosage form of detesting the dyestuff of agent.The color that discharges by the change dosage form can prevent that the misuser from using reformed dosage form.
Another kind makes the complicated known scheme of abuse comprise the antagonist that adds active component in dosage form, is naloxone or naltrexone with regard to opioid for example, or causes the chemical compound of physiological defense reaction, as the root of hippo (ipecac).
Yet, because in the past in most cases for the essential dosage form of pulverizing of the purpose that reaches abuse, so the purpose of this invention is to provide the method that a kind of preparation comprises the dosage form of the active component that may abuse, when correctly using the dosage form of this method acquisition, can guarantee required therapeutic effect, but, can not just the active component in this dosage form be transformed into the dosage form that is suitable for abusing through simple the pulverizing by the conventional available method of possible misuser.
This purpose reaches by the method for the solid dosage forms that prevents from according to preparation provided by the invention to abuse, this dosage form comprises at least a active substance that may be abused and at least a fracture strength binding agent more than or equal to 500N, described method comprise the mixture that will comprise active substance and binding agent be exposed to ultrasonic and power under.
Because the method according to this invention is used ultrasonic and-the quantitative at least a binding agent of fracture strength, make resulting dosage form also have fracture strength more than or equal to 500N, pulverizing this dosage form with conventional method like this may be with the very complicated pulverizing that maybe may prevent this dosage form, and has therefore prevented its abuse subsequently.
If pulverizing not exclusively, just can not be carried out parenteral, especially intravenous administration safely or extract active component and need spend the long time for the misuser, perhaps, when oral abuse, do not have " kick " owing to do not discharge simultaneously.
According to the present invention, pulverize and to be meant the breaking method that adopts the available routine of misuser, as mortar and pestle, hammer, short hammer or other are by applying the breaking method commonly used that power is pulverized.
Therefore, the method according to this invention produces and to be suitable for preventing active component, preferably has the dosage form of abuse of parenteral, per nasal and/or the per os of the active constituents of medicine of abuse potential.
Active component with abuse potential, the active constituents of medicine such as their dosage that preferably have abuse potential are well known by persons skilled in the art, and by their corresponding derivant, particularly esters of method of the present invention, ether or amide, or corresponding in each case physiologically acceptable chemical compound, particularly their salt or solvate forms and racemic compound, enantiomer or stereoisomer also can be in order to avoid abuses.Dosage form prepared in accordance with the present invention also is fit to comprise one or more active component, preferably only comprises a kind of active component.
The method according to this invention is particularly suitable for preventing to comprise narcosis analgesic, opiate, tranquilizer, the abuse of preferred benzodiazepine derivatives, barbiturates, stimulant and other narcotic active constituents of medicine.
The method according to this invention also is particularly suitable for preventing at least a opiate, tranquilizer or at least a being selected from
Dosage form according to the present invention is particularly suitable for preventing to be selected from oxycodone, hydromorphone, morphine and tramadol and their physiologically acceptable derivant or chemical compound, preferred their salt and solvate, the preferably abuse of the opium sample active component of its hydrochlorate or sulfate or methylphenidate or salt or solvate or physiologically acceptable derivant.
Also be particularly suitable for preventing to be selected from the abuse of following opiates active component according to dosage form of the present invention: (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl group)-phenol, (2R, 3R)-1-dimethylamino-3-(3-methoxyl group-phenyl)-2-methyl-pentane-3-alcohol, (1RS, 3RS, 6RS)-6-dimethylaminomethyl-1-(3-methoxyl group-phenyl)-cyclohexane extraction-1, the 3-glycol, (1R, 2R)-3-(2-dimethyl aminoethyl-cyclohexyl)-phenol, their physiologically acceptable salt, the preferred salt hydrochlorate, physiologically acceptable enantiomer, stereoisomer, diastereomer, racemic modification and their physiologically acceptable derivant, preferred ether, ester or amide.
These chemical compounds and preparation method thereof are described in EP-A-693475 and EP-A-780369 respectively.Corresponding explanation is incorporated by reference here and regard the part of disclosure as.
In order to reach the essential fracture strength of dosage form according to the present invention, at least to use a kind of natural or synthetic polymer (C), this polymer have by the fracture strength of using the 500N at least that the application's disclosed method measures and optional at least a fracture strength at least the wax of 500N (D) as binding agent.
Be selected from polyalkylene oxide, preferred polymethylene oxide, poly(ethylene oxide), poly(propylene oxide); At least a polymer of polyethylene, polypropylene, polrvinyl chloride, Merlon, polystyrene, polyacrylate and copolymer thereof and at least two kinds of described mixture of polymers are preferably used as polymer (C).
Preferred high-molecular weight thermoplastic polyalkylene oxide.Especially preferably have at least 0.5 million by what ftheoloqical measurements was determined, preferably at least 1 million, especially preferably at least 1 million to 15,000,000, the high-molecular weight poly(ethylene oxide) of at least 5 million molecular weight very particularly preferably.The viscosity model of these polymer is that the viscometer (No. 2/rotating speed of rotating shaft 2rpm) of RVF Brookfieid is measured in the aqueous solution of 5 weight %, be 4500 to 17600cP under 25 ℃, measuring viscosity with described viscometer (No. 1, rotating shaft or No. 3/rotating speed 10rpm) in the aqueous solution of 2 weight % is 400 to 4000cP or to measure viscosity with described viscometer (No. 2/rotating speed of rotating shaft 10rpm) in the aqueous solution of 1 weight % be 1650 to arrive 10000cP.
Polymer preferably uses powder type.They can be dissolved in the water.
In order to reach the essential fracture strength of dosage form prepared in accordance with the present invention, can also use at least a natural, semisynthetic or synthetic wax (D) as other binding agent, this wax has by using the fracture strength of the 500N at least that the application's disclosed method measures.Softening point is at least 60 ℃, and preferred at least 80 ℃ wax is preferred.Preferred especially Brazil wax and Cera Flava are preferred.More preferred babassu.Brazil wax is the native paraffin that obtains from the leaf of babassu, has at least 80 ℃ softening point.When also using the wax composition, it with at least a polymer (C) with a certain amount of use, so that dosage form prepared in accordance with the present invention has the fracture strength of 500N at least.
With respect to the gross weight of dosage form, the use amount of preferred adhesive composition is at least 20 weight %, preferred at least 35 weight %, preferred especially 50 to 99.9 weight %, very particularly preferably at least 60 weight %.
Also can use adjuvant material (B) in the method according to the invention.Operable adjuvant material (B) is those known conventional adjuvant materials that are used to prepare solid dosage forms.Preferred plasticizer as Polyethylene Glycol, influences the adjuvant material that active component discharges, and is preferred hydrophobic or hydrophilic, preferred hydrophilic polymer, very particularly preferably hydroxypropyl emthylcellulose and/or antioxidant.Suitable antioxidant is ascorbic acid, fourth hydroxyanisol, fourth hydroxy-methylbenzene, Ascorbate, single thioglycerol, phosphorous acid, vitamin C, vitamin E and derivant thereof, sodium sulfite, preferred especially fourth hydroxy-methylbenzene (BHT) or fourth hydroxyanisol (BHA) and alpha-tocopherol.
With respect to the gross weight of dosage form, the preferred 0.01-10 weight of the use amount of antioxidant %, preferred especially 0.03-5 weight %.
By uniting the binding agent that uses ultrasonic and fracture strength 〉=500N, make simple and can repeatedly use the method according to this invention to become possibility, so that this dosage form reaches certain fracture strength, pulverizing this dosage form with conventional method like this may be with complicated or prevented pulverizing to this dosage form to heavens, and has therefore prevented its abuse subsequently.
Use the method according to this invention, can obtain the dosage form of tablet or many granules form, preferably microplate, microcapsule, bead, microparticle, spheroid, pearl or ball optionally are pressed into tablet or are wrapped in the capsule.Many granules preferred size or size distribution arrive in the scope of 3mm 0.1, arrive in the 2mm scope particularly preferably in 0.5.
With the prepared according to the methods of the invention peroral dosage form is preferred.
Realize method of the present invention, comprise at first prepare at least a active component that may abuse (A), at least a binding agent with described fracture strength and optional at least a other as a) to f) listed preventing abuse the homogeneous mixture of chemical compound.In addition, also can be adjuvant material (B), for example the reagent of filler, plasticizer, sustained release, antioxidant, slipping agent or dyestuff are incorporated in this mixture.
Can realize by the help of conventional mixer mixing.For example, roller bearing blender, shake blender, shear mixer or arm mixer all are suitable.
After optional initial processing, with resulting mixture of powders be exposed to ultrasonic in.
During supersound process, preferably these mixture (preferably in shaping mould) directly contact with the sound level of Vltrasonic device, and promptly sound level touches this mixture.The preferred in the method according to the invention Vltrasonic device that uses as shown in Figure 1.
In accompanying drawing 1, (1) expression forcing press applies essential power by it, (2) transducer, and (3) amplifier, (4) sound level, (5) shaping mould, (6) bottom punching, (7) base plate, (8) and (9) are ultrasonic generator and control device.Vltrasonic device not only comprises a shaping mould and a base plate, but comprises several such unit, and sound level has been divided into the top punching of respective numbers.
During supersound process, keep 1kHz to 2MHz, preferred 10 to 75kHz, preferred especially 20 to 40kHz frequency.Carry out supersound process always, softening at least until binding agent.Said process preferably in the several seconds, particularly preferably at least 0.1 second, very particularly preferably in 0.1 to 5 second, was particularly finished in 0.5 to 3 second.
For reaching ultransonic purpose, mixture is placed shaping mould, sound level is introduced contacting with this mixture.
This mixture also can come molding by applying power.Preferably in supersound process or after with mixture forming.
If molding in above-mentioned Vltrasonic device need be assisted by shaping mould, bottom punching and sound level and be finished.For this reason, assisting down of forcing press (1), apply necessary power to mixture.In the method, the compaction of mixture is made its molding, preferably obtained final shape.For this molding, preferably with shaping mould, bottom punching and the shape that will reach as the perforated sound level adjustment in top, preferred final shape, wherein, and punching pattern and sound level pattern, promptly their opposing ends faces are complementary in form.Applying power by sound level on mixture indurates mixture and molding.
It is constant that the power that applies between shaping period preferably keeps, and ultrasonic optional can the variation.When in ultrasonic beginning, the energy that needs the input maximum possible is for example for plasticizing binding agent fast with when shortening preparation time, the preferred ultrasonication of using stagewise, so that preferably when beginning, promptly,, higher ultrasonic amplitude provides 30 to 60% of gross energy input by being set in the ultransonic phase I.
Ultrasonic and applied force can be guaranteed the even transmission of energy, so just can be fast and make mixture coagulates equably.In the method, resulting dosage form has 〉=fracture strength of 500N, therefore can not pulverize with the method for routine.
Before carrying out molding, also can by ultrasonic and applied force resulting granules be shaped to required dosage form, for example tablet then by the mixture granulation is carried out initial processing.
Granulation can be carried out in machinery well known by persons skilled in the art and device.
If the granulation of being carried out is a wet granulation, can be water or aqueous solution, for example ethanol/water or isopropanol are as granulation liquid.
Mixture or above-mentioned ready-made granule also can be used for the melt extrusion molding, and wherein mixture changes into melt by ultrasonic or applied force, extrudes by mould then.Here, suppose that sound level is a piston that guides the function of ultrasonic or applied force, just as in the piston injection machine.The thread that obtains in the method extends to required length down the auxiliary of known devices, and is in addition, optional by converting it into final shape with other ultrasonic applied force.
Can be by the calender line between two counterclockwise molding rollers, preferred applied force is shaped to final shape with extrudate.
But, also can preferably with suitable injection moulding casting mixture or granule be prefabricated into extrudate down the auxiliary of piston injection machine, be used for supersound process and applied force then.
As mentioned above, mixture from the binding agent that comprises at least a active component that may abuse and at least a fracture strength 〉=500N, preferred its powder type is shaped to the net shape of preparation, preferably directly suppress by applied force, wherein before making firmly or during with this mixture be exposed to ultrasonic down.The power of using is used for the power of molding corresponding to routine, for example is used for the sheet mold pressing or is corresponding net shape with the granule pressing mold.
According to the present invention, during applied force, the power of being used is at least 50N, preferred 200N at least, very particularly preferably 500N at least.
Necessary power also can be applied to this mixture under roller auxiliary.But the molding of dosage form preferably by carrying out with dosage form or by the direct pressing mold of the powder mixture of its corresponding particulate component that forms, is wherein preferably carried out supersound process between shaping period or before the molding.Carry out supersound process, softening up to binding agent, this process is generally finished to maximum 5 seconds time being less than 1 second, compresses this mixture to the fracture strength of this dosage form and reaches the degree of 500N at least.
After this mixture is carried out supersound process and applied force, also can in the tabletting of routine, make its final molding.Tablet prepared in accordance with the present invention also can be made the form of multilayer tablet.
In multilayer tablet, should prepare the layer that at least one comprises active component with supersound process and applied force.
Preparation in accordance with the present invention obtains dosage form and is characterised in that their hardness, and they can not be pulverized by the conventional pulverizing apparatus that uses of misuser.So in fact, the abuse of having got rid of oral or parenteral, particularly intravenous or per nasal.Yet, in order to prevent dosage form that preparation in accordance with the present invention obtains because surprising power and contingent pulverizing and/or grind any possible abuse in the situation, in preferred embodiments, these dosage forms can further comprise make abuse complicated or prevent to abuse reagent as the adjuvant material.
Therefore, the dosage form that preparation in accordance with the present invention obtains except one or more have the active component and at least a binding agent of abuse potential, also comprise at least a following component (a) to (f) as the adjuvant material:
(a) material of at least a stimulation nasal meatus and/or pharynx,
(b) at least a viscosifier, these viscosifier form a kind of gel by means of the liquid, aqueous of essential minimum and the extract that obtains from this dosage form, and this gel preferably when joining volume more liquid, aqueous, still can be identified intuitively,
(c) at least a antagonist with active component of abuse potential,
(d) at least a emetic,
(e) agent is detested at least a dyestuff conduct,
And/or
(f) at least a bitter substance.
Component (a)-(f) each be applicable to respectively in addition all that preparation in accordance with the present invention obtains prevent to abuse dosage form.Correspondingly, component (a) preferably is suitable for preventing nose, oral and/or parenteral, abuse in the preferred intravenous.Component (b) preferably is suitable for preventing parenteral, preferred especially intravenous and/or nose abuse, component (c) preferably is suitable for preventing nose and/or parenteral, preferred especially intravenous abuse, component (d) preferably is suitable for preventing parenteral, preferred especially intravenous and/or oral and/or nose abuse, component (e) are suitable for as preventing vision blockage oral or the parenteral abuse, and component (f) is suitable for preventing the abuse of oral or nose.Make the abuse of the dosage form that prevents that more effectively preparation in accordance with the present invention from obtaining become possibility at least a above-mentioned uniting of component according to the present invention.
For example, the dosage form that preparation in accordance with the present invention obtains also can comprise two or more combination of component (a)-(f), preferred (a) and (b) and randomly (c) and/or (f) and/or (e) or (a) and (b) and randomly (d) and/or (f) and/or (e).
In another embodiment, the dosage form that obtains of preparation in accordance with the present invention can comprise all (a)-(f) components.
If comprising, the dosage form that preparation in accordance with the present invention obtains prevents the component (a) abused, stimulate the material of nasal meatus and/or pharynx, then it is those any materials that cause physiological reaction when by nasal meatus and/or pharynx administration according to the present invention, described physiological reaction both can be to make misuser's unhappiness so that he does not wish maybe can not continue to take, as calcination, also can be the physiology opposing reaction that corresponding active component produces, as having increased nasal discharge or sneeze thus.The material that stimulates nasal meatus and/or pharynx when these are conventional is by parenteral, particularly during intravenous administration, can cause very offending sensation, or or even insupportable pain, make the misuser not wish maybe can not continue to take this material.
The specially suitable material of material that stimulates nasal meatus and/or pharynx be that those cause calcination, itch, think sneeze, secretions increases or these stimulate at least two kinds the material of combination.Conventional suitable material that uses and content are the known simple preliminary Test Identification of maybe can passing through for the technical staff.
Stimulate the material of the component (a) of nasal meatus and/or pharynx to be preferably based on one or more compositions of at least a hot material medicine or one or more plant part.
Corresponding hot material medicine is known to those skilled in the art, and teaching " Pharmazeutische Biologie-Drogenund ihre Inhaltsstoffe " second edition that doctor showed by Hildebert Wagner, revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982,82 pages, et seq,, in be described.The there is described accordingly by incorporated by reference, and is regarded as the part of disclosure.
One or more compositions at least a following hot material medicine can be added in the dosage form that preparation in accordance with the present invention obtains as component (a): Allii sativi bulbus (Bulbus Allii), Asari rhizoma cum herba (Radix Asari and leaf), Calami rhi-zoma (Rhizoma Acori Graminei), Capsici fructus (Fructus Capsici), Capsici fructus acer (chilly), Curcumae longaerhizoma (Radix Tulipae Gesnerianae), Curcumae xanthorrhizae rhizoma (Javanese Radix Tulipae Gesnerianae), Galangae rhizoma (Rhizoma Alpiniae Officinarum root), Myristicae semen (Semen Myristicae), Piperisnigri fructus (Pericarpium Zanthoxyli), Sinapis albae semen (Caulis et Folium Sinapis albee colza), Sinapis nigrisemen (black mustard colza), Zedoariae rhizoma (Rhizoma Curcumae root) and zingiberisrhizoma (race) are preferably selected from Capsici fructus (Fructus Capsici) especially, Capsici fructusacer (chilly) and Piperis nigri fructus (Pericarpium Zanthoxyli).
The composition of hot material medicine preferably includes O-methoxy (methyl) phenolic compounds, amide compound, mustard oil or sulfide or by they derived compounds.
Particularly preferably, at least a composition of hot material medicine is selected from myristicin, elemicin, isoeugenol, alpha-ararin, safrole, 1-ally-3,4-methy-lene dioxy benzene, gingerol, xanthorrhizol, capsaicin class (capsaicinoids), preferred capsaicin, capsaicin derivatives, as N-vanillyl-9E-octadecylene amide, dihydrocapsaicin, nor-dihydrocapsaicin, homocapsaicin, nor-capsaicin and nor-capsaicin (nornorcapsaicin), piperine, anti-preferred-piperine, the sulfo-gluconate, be preferably based on non-volatile mustard oil, be preferably based on right-acrinyl mustard oil especially, methyl mercapto mustard oil or sulfonyloxy methyl mustard oil and these composition derived compounds.
Dosage unit is meant isolating or separable administration unit, for example tablet or capsule.
In each case, with respect to the gross weight of dosage unit, the dosage form that preparation in accordance with the present invention obtains can preferably comprise the plant part of the corresponding hot material medicine of 0.01 to 30 weight %, especially preferably comprises 0.1 to 0.5 weight %.
If use one or more compositions of corresponding hot material medicine, then gross weight their content in dosage unit according to the present invention with respect to dosage unit is preferably 0.001 to 0.005 weight %.
Another scheme of dosage form abuse that prevents according to the present invention is at least a viscosifier as the component that further prevents to abuse (b) are joined in the dosage form, form gel by means of the essential minimum liquid, aqueous and extract that obtains from this dosage form, this gel can not be used by safety clothes in fact, and preferably when it being joined volume more liquid, aqueous middle, still can identify intuitively.
In order to reach purpose of the present invention, intuitively identification be meant when preferably be incorporated into by means of the essential minimum liquid, aqueous formed gel that contains active component by means of hypodermic needle under 37 ℃ more volume is liquid, aqueous the time, this gel still is insoluble and viscosity basically, and can not be with can be by parenteral, particularly the mode of intravenous safe administration is directly disperseed.This material preferably kept 1 minute at least, preferred at least 10 minutes identification directly perceived.
The viscosity increase of extract makes that it is more difficult or even may not pass pin or injected.If the gel maintenance can intuitively be discerned, this means when the gel that obtains is incorporated into more volume liquid, aqueous in, as when being expelled in the blood, originally it keeps the form of the line of big viscosity, and in fact it can be broken down into littler fragment, it can not be with can be by parenteral, and particularly the mode of intravenous safe administration is disperseed or even dissolving.With the component (a) of at least a optional existence or (c)-(e) combination, also can cause the obstruction of offending calcination, vomiting, taste bad will and/or vision.
Therefore, such gel intravenous administration most probable is caused severe impairment to misuser's health.
In order to verify whether a kind of viscosifier are suitable as component (b) and are used for the dosage form that preparation in accordance with the present invention obtains, and active component is mixed with viscosifier, and to be suspended in temperature be in 25 ℃ the 10ml water.If the gel of Xing Chenging satisfies above-mentioned condition like this, the abuse of the dosage form that then corresponding viscosifier are suitable for preventing or avoid that preparation in accordance with the present invention obtains.
If component (b) is added in the dosage form that preparation in accordance with the present invention obtains, then one or more viscosifier of Shi Yonging are selected from: the sodium carboxymethyl cellulose (Avicel that contains 11 weight % RC591) microcrystalline Cellulose, sodium carboxymethyl cellulose (Blanosel , CMC-NaC300P , Frimulsion BLC-5 , Tylose C300 P ), polyacrylic acid (Carbopol 980 NF, Carbopol 981), carob flour (Cesagum LA-200, Cesagum LID/150, Cesagum LN-1), pectin, preferably Fructus Citri tangerinae fruit or Fructus Mali pumilae (Cesapectin HMMedium Rapid Set), waxy corn starch (C *Gel 04201 ), sodium alginate (FrimulsionALG (E401) ), guar gum powder (Frimulsion BM , Polygum 26/1-75 ), ι carrageenin (Frimulsion D021 ), karaya, Gellan gum (Keicogel F , Kelcogel LT 100 ), (Meyprogat 150 for galactomannan ), (Polygum 43/1 for tara stoneflour ), propylene glycol alginate (Protanal-Ester SD-LB ), hyaluronate sodium, Tragacanth, tara natural gum (Vidogum SP 200 ), the polysaccharide welan natural gum (K1A96), xanthan gum class of fermentation for example xanthan gum (Xantural 180 ).The xanthan gum class is particularly preferred.The title of mentioning in bracket is the trade (brand) name of commercial known substance.Usually, with respect to the gross weight of dosage form, 0.1 to 20 weight %, the described viscosifier of preferred especially 0.1 to 15 weight % are enough to satisfy above-mentioned condition.
The component that provides (b) viscosifier are preferably with every dosage unit, and the amount 1.5mg of promptly every administration unit is present in the dosage form that preparation in accordance with the present invention obtains.
In a special preferred embodiment of the present invention, be by means of essential minimum liquid, aqueous when from dosage form, extracting as the viscosifier of component (b), it forms those of gel that envelope has air bubble.The gel that obtains can offer the warning of possible another vision of misuser, and stop him or she through this gel of parenteral administration like this by muddy phenomenon identification.
Polymer (C) also can be randomly as viscosifier another kind of and water formation gel.
In the dosage form that preparation in accordance with the present invention obtains, also be possible spatially in the mode that is separated from each other with viscosifier and other composition.
Abuse in order to stop and to prevent, the dosage form that preparation in accordance with the present invention obtains can further comprise component (c), one or more antagonisies that promptly have one or more active component of abuse potential, wherein all the other compositions of the preferred dosage form that spatially obtains with preparation in accordance with the present invention of this antagonist are isolating, and they can not produce any effect when correct use.
Be used to prevent that the appropriate antagonist of active component abuse from being well known by persons skilled in the art, and may reside in the dosage form that preparation in accordance with the present invention obtains, or with corresponding derivant, particularly the form of ester or ether or under every kind of situation with corresponding physiologically acceptable chemical compound, particularly salt or the solvate forms with them exists.
If the active component that exists in the dosage form is an opioid, then used antagonist is preferably from naloxone, naltrexone, nalmefene, nalid, nalmexone, nalorphine or naphthalene morphine, under every kind of situation,, particularly exist with alkali, salt or solvate forms randomly with corresponding physiologically acceptable compound form.Corresponding antagonist, when as component (c) when providing, its preferred amounts is every dosage form, promptly every administration unit 〉=1mg, preferred especially 3-100mg, very particularly preferably 5-50mg.
If the dosage form that preparation in accordance with the present invention obtains comprises stimulant as active component, this antagonist tranquilizer preferably then, the preferred at least a chemical compound that is selected from haloperidol, phenergan, fluphenazine, perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixene, zuclopenthixol, flupentixol, prothipendyl, zotepine, benperidol, pipamperone, melperone and bromperidol.
The dosage form that preparation in accordance with the present invention obtains preferably includes the antagonist of conventional therapy dosage well known by persons skilled in the art, and the 2-3 that special preferred dose is every administration unit routine dose doubly.
If in order to stop or to prevent to abuse the dosage form that preparation in accordance with the present invention obtains, also used component (d), then can prepare and proceed to less a kind of emetic, so that itself and other composition exists in the mode that is separated from each other arrangement on the space, when correct use, it can not had an effect in health.
Be used to prevent that the suitable emetic of active component abuse from being well known by persons skilled in the art, and can be used for or with corresponding derivant, particularly the form of ester or ether or under every kind of situation with physiologically acceptable chemical compound, particularly with their salt or the solvate forms preparation that is used for dosage form according to the present invention.
One or more compositions based on hippo (hippo) root, the emetic that is preferably based on the composition ipecine can preferably be present in the dosage form that preparation in accordance with the present invention obtains, as in that doctor showed by Hildebert Wagner professor " as described in the Pharmazeu tische Biologie-Drogenund ihre Inhaltsstoffe ' ' second edition; revised edition; Gustav Fischer Verlag, Stuttgart-New York, 1982; 82 pages, et seq--.It is described accordingly by incorporated by reference, and is regarded as the part of disclosure.
The dosage form that preparation in accordance with the present invention obtains can preferably include the ipecine as component (d), and preferred amounts is every dosage form, promptly every administration unit 〉=3mg, preferred 〉=10mg, more preferred 〉=20mg especially.
Apomorphine also can be preferably used as equally and prevent the emetic abused, and preferred amounts is every dosage form, promptly every administration unit 〉=3mg, preferred 〉=5mmg, more preferred 〉=every administration unit of 7mg especially.
If the dosage form that preparation in accordance with the present invention obtains comprises the component (e) as the auxiliary substance that further prevents to abuse, use such dyestuff to cause that corresponding aqueous solution is painted very dark, especially when attempting to be parenteral, preferred intravenous administration and when extracting active component paintedly can play the effect that stops possible misuser.Also can be by this painted prevention the oral abuse that begins of the water extraction by active component routinely.Stop essential suitable dyestuff and content in WO03/01 5531, can find.Wherein openly should be regarded as a part disclosed by the invention accordingly, and therefore incorporated by reference.
If the dosage form that preparation in accordance with the present invention obtains comprises the component (f) as the auxiliary substance that further prevents to abuse, the taste that then adds at least a bitter substance and therefore destroyed dosage form also can prevent the abuse of oral and/or per nasal.
The suitable bitter substance and the effective dose of use can be found in US-2003/0064099A1, wherein openly should be considered as accordingly the application's disclosure, and therefore incorporated by reference.Suitable bitter substance preferred fragrance oil, preferred Oleum menthae, Eucalyptus oil, Semen Armeniacae Amarum oil, menthol, fruit aroma material, preferred fragrance matter is selected from Fructus Citri Limoniae, Fructus Citri tangerinae, Citrus aurantium Linn., Fructus Citri grandis or their mixture, and/or denatonium benzoate (Bitrex ).Denatonium benzoate is particularly preferred.
According to further embodiment, the dosage form that obtains according to the present invention not only can be tablet or capsule form, and can be oral cavity osmotic therapeutic system (OROS) form, preferably also exist at least a other prevent the component (a)-(f) abused.
If in the dosage form that preparation in accordance with the present invention obtains, there is component (c) and/or (d) and/or (f), must be noted that and guarantee that they prepare in this way or exist with described low dosage, promptly when correct administration, described dosage form can not damaged patient in fact or is destroyed the effectiveness of active component.
If the dosage form that preparation in accordance with the present invention obtains comprises component (d) and/or (f), then must select, so that when correct oral administration, can not cause negative interaction to dosage.But,, then can cause nausea, want vomiting or taste bad will if under the situation of abuse, surpass the dosage of being estimated.Under correct case of oral administration, component that patient still can tolerate (d) and/or certain content (f) can be by those skilled in the art by simply tentatively measuring.
Yet; do not come down to the impossible fact of pulverizing if do not consider the dosage form that preparation in accordance with the present invention obtains; then can and/or (d) and/or (f) provide protection with component (c) for dosage form; these components should preferably be used with sufficiently high dosage; make that they bring intensive negative interaction to the misuser when abuse.This can be preferably by with at least a active component or various active composition and component (c) and/or (d) and/or (f) space separate and obtain, wherein this active component or these active component are present at least one subunit (x), and component (c) and/or (d) and/or (f) be present at least one subunit (Y), and wherein, when the correct administration of dosage form, component (c), (d) and (f) can the generation effect when taking and/or in health, and all the other components, particularly component (C) of preparation are the same with randomly (D).
If the dosage form that preparation in accordance with the present invention obtains comprises component (c) and (d) or (f) at least 2 kinds, then these can each all be present in the same or different subunits (Y).Can be preferably, when they existed, all components (c) and (d) and (f) were present in one and the identical subunit (Y).
In order to reach purpose of the present invention, subunit is a solid preparation, in each case, except conventional auxiliary substance well known by persons skilled in the art, it comprises active component, at least a polymer (C) and the optional component (D) that exists and there is component (a) and/or (b) and/or (e) in optional at least a choosing wantonly, or the component (a) of at least a polymer (C) and randomly (D) and antagonist and/or emetic and/or component (e) and/or component (f) and randomly at least a optional existence under every kind of situation and/or (b).Here must be noted that and guarantee that each subunit will prepare according to aforementioned method.
In the dosage form that preparation in accordance with the present invention obtains with the component (c) among active component and subunit (X) and (Y) (d) or a significant advantage of (f) separating preparation be: when the correct administration, component (c) and/or (d) and/or (f) when taking or in health, be difficult to discharge, perhaps burst size is very little, therefore, they are by patient body the time, can not damage patient or influence therapeutic effect, they only are released to the site that they can not be absorbed useful effect in large quantities.When the correct administration of this dosage form, preferred almost without any component (c) and/or (d) and/or (f) be discharged in patient's the health, perhaps they can not noticed by patient.
It will be understood to those of skill in the art that aforesaid condition can change with the preparation of the specific component (c), (d) and/or function (f) and the subunit that use or the difference of dosage form.The best preparation that is used for particular dosage form can be by simply tentatively measuring.Crucial is that subunit comprises adhesive component, i.e. polymer (C) and randomly component (D), and prepare in described mode.
If against one's expectation, in order to abuse active component, the misuser successfully will pulverize (this dosage form is included in the component (c) and/or (e) and/or (d) and/or (f) in the subunit (Y)) according to dosage form of the present invention, and obtain powder with suitable extractant extraction, active component not only then, and specific component (c) and/or (e) and/or (f) and/or (d) will obtain with the isolating form of active component with a kind of being difficult for, like this, when taking the dosage form that has changed without authorization, during particularly oral and/or parenteral, when taking and/or in health, will produce corresponding to component (c) and/or (d) and/or negative interaction (f) to the misuser, perhaps when attempting to extract active component, paintedly will play a role and therefore prevent the abuse of this dosage form as blocker.
Wherein this active component or these active component and component (c), (d) and/or (e) spatially be isolating, the dosage form that preferably is formulated in the different subunits can be prepared by different modes, wherein each can exist in according to dosage form of the present invention in the spatial arrangements mode of relative to each other wishing arbitrarily in corresponding subunit, and condition is the condition that satisfies aforementioned component (c) and/or (d) discharge.
It will be understood to those of skill in the art that, the optional component (a) that exists and/or (b) can preferably be formulated in the dosage form that preparation in accordance with the present invention obtains, both can be all at specific subunit (X) with (Y), also can in form, exist corresponding to subunit (X) and independent subunit (Y), condition is to prevent to abuse and the release of the active component under the situation of correct administration can not destroyed by the character of preparation, and polymer (C) and randomly (D) be preferably included in the preparation, in order to obtain necessary hardness, aforementioned method prepares said preparation according to the present invention.
In an embodiment preferred of the dosage form that obtains according to the present invention, subunit (X) and (Y) exist with the multiparticle form, wherein preferred microplate, microcapsule, micropill, granule, spheroid, pearl or ball, and subunit (X) is selected identical form with subunit (Y), be shape, can not and (Y) separate subunit (X) by for example mechanical selection like this.This multiparticle form preferred size is in 0.1 to 3mm scope, and preferred 0.5 to 2mm.
Subunit in the multiparticle form (X) and (Y) also can preferably be packaged in the capsule or be compression molded into tablet, wherein final preparation in each case is to carry out with described method, also to be retained in the dosage form that makes with subunit (X) with (Y).
Identical shaped many granules subunit (X) and (Y) should also can not intuitively identify each other, like this, the misuser can not be by simple selection with they separated from one another coming.This for example can obtain by using identical coating, and described coating also can mix other function except the function with camouflage, as the slow release of one or more active component or the effect of final opposing gastric acid is provided for specific subunit.
The multiparticle subunit also can be made peroral dosage form such as slurry or the suspension in pharmaceutically safe suspension media.
In another preferred embodiment of the present invention, subunit (X) and (Y) arrange with layer respect to one another in each case.
In order to reach this purpose, lamellated subunit (X) and (Y) preferably horizontal or vertical relative to one another arrangement, wherein in each case, one or more lamellated subunits (X) and one or more lamellated subunit (Y) can exist in dosage form, so that except preferred layer order (X)-(Y) or (X)-(Y)-(X), also can consider any layer order that other needs, optional with contain component (a) and/or layer combination (b).
The preferred dosage form that another preparation in accordance with the present invention obtains is, wherein subunit (Y) has formed a core of being sealed by subunit (X) fully, and wherein stratum disjunctum (Z) may reside between the described layer.Such structure also preferably is suitable for aforementioned multiparticle form, wherein subunit (X) and (Y) and the optional stratum disjunctum (Z) that exists must satisfy requirement according to hardness of the present invention, they are formulated in one and the identical multiparticle form.In the further preferred embodiment according to the inventive method, subunit (X) forms core, and it is encapsulated in the subunit (Y), and wherein the latter comprises at least one passage that leads to the dosage form surface from core.
The dosage form that preparation in accordance with the present invention obtains can be between one deck subunit (X) and one deck subunit (Y), in each case, randomly comprise one or more layers, the stratum disjunctum (Z) of preferred one deck swellable, this stratum disjunctum have subunit (X) and the isolating effect in subunit (Y) space.
The lamellated subunit (X) of the horizontal or vertical arrangement of small part and (Y) and the stratum disjunctum (Z) of optional existence if the dosage form that preparation in accordance with the present invention obtains comprises, then this dosage form preferably adopts tablet or laminate form.
In a particularly preferred embodiment, whole free surface of subunit (Y) and randomly subunit (X) can stop component (c) and/or (e) and/or (d) and/or the barrier layer that (f) discharges (Z ') coating with one deck at least to the small part free surface to the optional of small part free surface and the optional stratum disjunctum (z) that exists.This barrier layer (Z ') also can be prepared and prepare in a certain way to satisfy according to stiffness conditions of the present invention.
The particularly preferred embodiment of the dosage form that another preparation in accordance with the present invention obtains comprises the subunit layer (X) of horizontal or vertical arrangement and (Y) and be arranged in promoting layer of one deck at least (p) and stratum disjunctum (Z) randomly between them, wherein in this dosage form to whole free surface by subunit (X) and the layer structure (Y) formed, promoting layer and the optional stratum disjunctum (Z) that exists provide semi permeable coating, it is for release medium, promptly Chang Gui physiological fluid is permeable, but for active component and component (c) and/or (d) and/or (f) come down to impermeablely, and wherein this coating comprises that at least one is used for the opening at subunit (X) zone release of active ingredients.
Corresponding dosage forms, for example so-called oral osmotic therapy system (OROS) is well known by persons skilled in the art, suitable material that is used to make and method and other content are known from US4612008, US 4765989 and US 4783337.Corresponding explanation is hereby incorporated by, and is considered as the part of disclosure.Importantly, regulate these systems in the preparation according to the present invention, so that their fracture strength 〉=500N.
In another preferred embodiment, the subunit of dosage form prepared in accordance with the present invention (X) is a tablet form, the optional quilt in its edge surface and two the main faces contain component (c) and/or (d) and/or barrier layer (f) (Z ') cover.
It will be understood to those of skill in the art that the subunit (X) that is used for preparing dosage form according to the present invention or (Y) and the auxiliary substance of the optional stratum disjunctum (Z) that exists and/or barrier layer (Z ') will with function, administering mode and the optional component (a) that exists of the arrangement of the dosage form that obtains in preparation in accordance with the present invention and/or (b) and/or (e) and component (c) and/or (d) and/or the function of specific active ingredient (f) change.The material with essential attributes in each case is known for those skilled in the art.
As fruit component (c) and/or (d) and/or (f) from the subunit (Y) of dosage form, discharge and be capped thing according to the present invention, the words that preferred barrier layer stops, then this subunit can be made up of conventional material well known by persons skilled in the art, condition be it comprise at least a polymer (C) and randomly (D) to satisfy the essential fracture strength of dosage form prepared in accordance with the present invention.
If do not provide corresponding barrier layer (Z ') to stop component (c) and/or (d) and/or release (f), then should select the material of subunit so that from subunit (Y) discharge specific component (c) and/or (d) come down to impossible.
The foregoing material that is suitable for preparing barrier layer can be preferred for achieving this end.
Preferable material is selected from following material: alkylcellulose, hydroxy alkyl cellulose, glucosan, scleroglucan, mannan, xanthan gum class, poly-[two (right-the carboxyl phenoxy group)] propane and decanedioic acid, preferred molar ratio is 20: the 80 (title that is purchased: Polifeprosan 20 ), carboxymethyl cellulose, cellulose ether, cellulose esters, NC Nitroncellulose, its polymer, polyamide, Merlon, poly-alkylene hydrocarbon, poly alkylene glycol, polyalkylene oxide, polyalkylene terephthalate, polyvinyl alcohol, polyvinylether, polyvinyl ester, halogenated polyethylene, polyglycolide, polysiloxanes and polyurethanes and their copolymer based on (methyl) acrylic acid and ester thereof.
Specially suitable material can be selected from: methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxy butyl methyl cellulose, cellulose acetate, cellulose propionate is (low, in or high molecular), cellulose-acetate propionate, cellulose acetate-butyrate, Cellacefate, carboxymethyl cellulose, cellulose triacetate, cellulose sodium sulfate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, the own ester of polymethylacrylic acid, polymethylacrylic acid isodecyl ester, polylauryl methacrylate, the polymethyl acid phenenyl ester, polymethyl acrylate, the polyacrylic acid isopropyl ester, polyisobutyl acrylate, poly-propanoic acid octadecane ester, polyethylene, low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene, Polyethylene Glycol, poly(ethylene oxide), poly terephthalic acid ethylidene ester, polyvinyl alcohol, PVI polyvinyl isobutyl ether, polyvinyl acetate and polrvinyl chloride.
Particularly preferred copolymer can be selected from: the copolymer of copolymer, ethylene methacrylic ether and the maleic anhydride of the copolymer of the copolymer of butyl methacrylate and isobutyl methacrylate, ethylene methacrylic ether and high-molecular weight maleic acid, ethylene methacrylic ether and maleic acid list ethyl ester and the copolymer of vinyl alcohol and vinyl acetate.
The other materials that is particularly suitable for preparing barrier layer is polyester urethane (DE 19822979), polyhydroxyalkanoatefrom, particularly poly butyric ester, poly-hydroxyl valerate, casein (DE 4309528), polyactide and the copolymerization lactide (EP 0980894 A1) of starch filled polycaprolactone (WO98/20073), aliphatic polyester amide (DE 19753534 A1, DE 19800698 A1, EP0820698A1), aliphatic series and aromatics.Corresponding explanation is hereby incorporated by reference and is considered as the part of disclosure.
Aforementioned material can randomly mix with other auxiliary substances of routine well known by persons skilled in the art, preferably certainly: the triglyceride of glyceryl monostearate, semisynthetic triglyceride derivative, semisynthetic glyceride, castor oil hydrogenated, Palmic acid tristerin, Glyceryl Behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, Talcum, sodium behenate, boric acid, colloidal silica, fatty acid, replacement, glyceride, polyether polyols and their derivant.
If the dosage form that obtains according to the present invention comprises stratum disjunctum (Z '), described layer can preferably be made up of the aforementioned material that is used for the barrier layer description as unlapped subunit (Y).It will be understood to those of skill in the art that active component or component (c) and/or (d) from specific subunit, discharge to be THICKNESS CONTROL by stratum disjunctum.
The dosage form that obtains according to the present invention has shown the effect that the control active component discharges.Preferably be suitable for being administered twice to the patient every day.
The dosage form that preparation in accordance with the present invention obtains can comprise one or more active component that may abuse that exist with the slow release form to small part, wherein slow release can be by means of the material of routine well known by persons skilled in the art and method and is reached, for example, active component is embedded in the sustained-release matrix, or uses one or more sustained release coatings.But, the release of active component must be controlled, to satisfy aforementioned condition in each case, for example, under the situation of the correct administration of dosage form, a kind of active component or various active composition have just discharged before the performance detrimental effect fully in the optional component (c) that exists and/or (d) in fact.The interpolation that influences the material of controlled release in addition must can not destroy necessary hardness.
The controlled release of the dosage form that obtains according to the present invention is preferably realized by active component is embedded in the substrate.Control the release of active component as the auxiliary substance of host material.Host material can be, for example hydrophilic material, active component mainly discharge from this material by diffusion, and perhaps hydrophobic material, active component mainly discharge from this material by the diffusion of the hole in the substrate.
Physiologically acceptable hydrophobic material well known by persons skilled in the art can be used as host material.Polymer, special preferred cellulose ether, cellulose esters and/or acrylate are preferably used as the hydrophilic group material.Ethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxy methocel, poly-(first) acrylic acid and/or their derivant more especially preferably are used as host material as their salt, amide or ester.
By the host material of hydrophobic material preparation, also be preferred as hydrophobic polymer, wax, fat, long-chain fatty acid, aliphatic alcohol or corresponding ester or ether or their mixture.The list of C12-C30 fatty acid or two glyceride and/or C12-C30 aliphatic alcohol and/or wax or their mixture are preferably used as hydrophobic material especially.
Using aforementioned hydrophilic and hydrophobic material also is possible as host material.
Binding agent, promptly component (C) and the optional component (D) that exists are used to realize the fracture strength according to the 500N at least of necessity of the present invention, it also can be used as other host material in addition and uses.
If the dosage form that obtains according to the present invention is to be used for oral administration, it also can preferably include a kind of coating, and this coating has resistant function to gastric juice, and to discharge the function dissolving of environment PH.By the method for this coating, can guarantee that dosage form according to the present invention is passed stomach and not dissolved, and active component only is discharged in the small intestinal.The coating of opposing gastric juice preferably dissolves under the pH value between 5 and 7.5.
Be used for the active component controlled release and be used to resist the corresponding material of coating of gastric juice and method to those skilled in the art, for example can be from Kurt H-Bauer, K-Lehmann, Hermann P-Osterwald, Rothgang, " pharmaceutical dosage form-principle of coating, manufacturing technology, biopharmacy, experimental technique and the raw material " the 1st edition of Gerhart work, 1998, learn among the MedpharmScientitic Publishers.Corresponding explanatory note is hereby incorporated by reference, and is considered as the part of disclosure.
Measure the method for fracture strength
In order to verify whether polymer can be used as binding agent, it is component (C) or (D), is 10mm with the power of 150N becoming diameter corresponding to the temperatures of the softening point of this polymer at least with polymer, and thick is the sheet of 5mm, and measures by means of the DSC figure of this material.The tablet that adopts this mode to make, fracture strength are according to being disclosed in European Pharmacopoeia 1997, the 143-144 page or leaf, and the method that the 2.9.8 method is measured the fracture strength of tablet uses the instrument that describes below to measure.
The instrument that is used to measure that uses is " Zwick z 2-5 " material testing machine, Fmax=2.5KN maximum tension 11 50mm set 1 post and 1 axle, in the gap of the 100mm of back, and adjustable test speed 0.1 and 800mm/ minute between, use TT﹠C software.Measure and use pressure piston with screw rod insert and cylinder (diameter 10mm), force transducer, Fmax.1kN, diameter=8mm, 0.5 grade of 10N, 1 grade of 2N to ISO 7500-1, and (all instruments are purchased the ﹠amp in Zwick GmbH to have manufacturing test quality certification M to DIN 55350-1 8 (the total power Fmax=1.45kN of Zwick); Co.KG, Ulm, Germany) with being numbered BTC-FR 2.5TH.D09 tester, be numbered the force transducer of BTC-LC 0050N.P01, be numbered the centrifugal device of BO70000 S06.
Fig. 2 shows the test of the fracture strength of tablet, especially for this purpose before test and the adjusting device (6 ') of tablet (4 ') in the test.For this reason, using the instrument (not shown) by the power of two two-part clamp apparatus (2 ') is placed on tablet (4 ') between upward pressure plate (1 ') and the lower pressure plate (3 '), in case established the placement and the centrifugal necessary spacing (5 ') of the tablet that will measure, all used lower pressure plate in each case it is clamped tightly.Described spacing (5 ') can by place on the pressure plare of clamping device level outward or mobile inward two parts clamping device establish.
The tablet that is regarded as can resisting fracture under specific load not only comprises those not fractures, comprises that also those can stand the tablet of plastic deformation under pressure.
The fracture strength of definite dosage form that obtains according to the present invention comprises according to described method and measuring, and wherein test is not the dosage form of tablet yet.
Below with reference to embodiment the present invention is described.These explanations only provide by the mode of embodiment, rather than limit general concept of the present invention.
Embodiment:
Embodiment 1
Component Every Inferior by the gross
Tramadol hydrochloride 205.0mg 6.13g
Poly(ethylene oxide), NF MW 7 000 000 (Polyox WSR 303, Dow Chemicals) 381.0mg 11.38g
Gross weight 586.0mg 17.51g
Tramadol hydrochloride and poly(ethylene oxide) powder is mixed in free fall type blender.Use following supersound process and applied force with this mixture tablet forming then.For this purpose, use following machine:
Forcing press: Branson WPS, 94-003-A, by compressed air promote (BransonUltraschall, Dietzenbach, Germany)
Generator (2000W): Branson PG-220A, 94-001-A analog (BransonUltraschall)
The diameter of sound level is 12mm.The forcing press surface is smooth.
Mixture is placed the shaping mould of diameter 12mm.The bottom punching on the applanation surface with diameter 12mm has been formed on the bottom of this shaping mould.
Select following parameter to carry out the plasticization of mixture:
Frequency: 20Hz
Amplitude: 50%
Power: 250N
Supersound process and applied force continue 0.5 second, in the auxiliary supersound process and the applied force of carrying out simultaneously down of sound level.
Utilize described device to use described method to determine the fracture strength of tablet.When using the power of 55N, do not rupture.Tablet uses hammer not pulverized, and can not be pulverized under helping with pestle and alms bowl.
Active component is to measure during having the paddle agitator of plummet according to European Pharmacopoeia from the release in vitro of preparation.The temperature of release medium is 37 ℃, and the blender rotating speed is 75 minutes-1.Used release medium is 600ml intestinal juice, pH6.8.Determine to be discharged at any one time under every kind of situation the amount of the active component in the medium with spectrophotography.
Time The amount tramadol of the active component that discharges
30 minutes 13％
240 minutes 51％
480 minutes 76％
720 minutes 100％
Embodiment 2
Component Every Inferior by the gross
Tramadol hydrochloride 100.0mg 10.0g
Poly(ethylene oxide), NF MW 7 000 000 (Polyox WSR 303, Dow Chemicals, fine powder) 200.0mg 20.0g
Gross weight 300.0mg 30.0g
Tramadol hydrochloride and poly(ethylene oxide) powder are blended into powder in free fall type blender.Then, as described in embodiment 1, this mixture mold pressing is in blocks with supersound process and applied force.For this purpose, use following machine:
Forcing press: Branson 2000 aemc (Branson Ultraschall, Dietzenbach, Germany)
Generator (2000W): Branson 2000b, digital 20:2.2 (Branson Ultraschall
The diameter of sound level is 10mm, and the concave of its curvature is 8mm.
Select following parameter, in 3 stages with mixture plasticising with compress:
Phase I:
Amplitude level: 75% carried out 0.15 second
Frequency: 20Hz
Power: 970N
Second stage:
Amplitude level: 32.5% carried out 0.55 second
Frequency: 20Hz
Power: 970N
Phase III:
Power: 970N carried out 2.3 seconds
Do not carry out supersound process
Utilize described device to use described method to determine the fracture strength of tablet.When using the power of 500N, do not rupture.Can not pulverize described tablet with hammer or with pestle and alms bowl.
The release in vitro of active component is to measure in having the paddle agitator of plummet according to European Pharmacopoeia.The temperature of release medium is 37 ℃, and the blender rotating speed is 75 minutes -1Used release medium is 600ml intestinal juice, pH6.8.Determine to be discharged at any one time under every kind of situation the amount of the active component in the medium with spectrophotography.
Time The amount tramadol of the active component that discharges
30 minutes 17.1％
240 minutes 60.6％
480 minutes 84.0％
720 minutes 94.2％

Claims (28)

1. method for preparing the solid dosage forms that prevents to abuse, this dosage form comprises at least a active component (A) that may be abused and at least a fracture strength binding agent more than or equal to 500N, it is characterized in that, the mixture that comprises active component and binding agent be exposed to ultrasonic and power under.
2. according to the method for claim 1, it is characterized in that this dosage form is a peroral dosage form, preferably tablet.
3. according to the method for claim 1, it is characterized in that this dosage form is the dosage form of many particle form, preferably microplate, micropill, granule, microgranule, spheroid, pearl or ball optionally are molded into tablet or are packaged in the capsule.
4. the method arbitrary according to claim 1 to 3 is characterized in that employed binding agent is at least a synthetic or natural polymer (C) and randomly at least a wax (D), and wherein its fracture strength is 500N at least in each case.
5. the method arbitrary according to claim 1 to 4, it is characterized in that used polymer (C) is at least a polymer that is selected from poly(ethylene oxide), polymethylene oxide, poly(propylene oxide), polyethylene, polypropylene, polrvinyl chloride, Merlon, polystyrene, polyacrylate, its copolymer and composition thereof, preferred poly(ethylene oxide).
6. the method arbitrary according to claim 1 to 5 is characterized in that the molecular weight of poly(ethylene oxide) (C) is at least 0.5 * 10 6
7. according to the method for claim 6, it is characterized in that the molecular weight of poly(ethylene oxide) (C) is at least 1 * 10 6, preferred 1 * 10 6-1.5 * 10 7, especially preferably at least 5 * 10 6
8. the method arbitrary according to claim 4 to 7 is characterized in that employed wax (D) is that at least a softening point is at least 60 ℃, preferred at least 80 ℃ natural, semi-synthetic or synthetic wax.
9. method according to Claim 8 is characterized in that employed wax (D) is Brazil wax or Cera Flava.
10. according to method arbitrary among the claim 1-9, it is characterized in that the use amount of one or more adhesive components (C) and optional (D), make that the fracture strength of resulting dosage form is 500N at least.
11. according to the method for claim 10, it is characterized in that the gross weight with respect to dosage form, the amount of employed one or more adhesive components is at least 20 weight %, preferred at least 35 weight %, preferred especially 50 to 99.9 weight %.
12. according to the method for claim 11, it is characterized in that the gross weight with respect to dosage form, the amount of employed one or more adhesive components is at least 60 weight %.
13. the method arbitrary according to claim 1 to 12 is characterized in that employed active component (A) is at least a active component that is selected from opiates, tranquilizer, stimulant, barbiturate and other anesthetis and its physiologically acceptable derivant.
14., it is characterized in that employed physiologically acceptable derivant is salt, solvate, ester, ether or amide according to the method for claim 13.
15., it is characterized in that the employed active component that may abuse (A) is oxycodone, morphine, hydromorphone, tramadol, methylphenidate or their physiologically acceptable salt, the preferred salt hydrochlorate according to the method for claim 13 or 14.
16. the method arbitrary according to claim 1 to 15 is characterized in that employed conventional adjuvant material (B) also is used to prepare this dosage form.
17., it is characterized in that the adjuvant material (B) that also uses is a plasticizer, preferred low-molecular-weight Polyethylene Glycol, antioxidant and/or hydrophilic polymer and/or hydrophobic polymer according to the method for claim 16.
18. the method arbitrary according to claim 1 to 17, it is characterized in that applied supersonic frequency be 1kHz to 2MHz, preferred 10 to 75kHz.
19., it is characterized in that applied supersonic frequency is 20 to 40kHz according to the method for claim 18.
20. the method arbitrary according to claim 1 to 19 is characterized in that during supersound process, and direct contact is arranged between the sound level of mixture and Vltrasonic device.
21., it is characterized in that this sound level touches this mixture according to the method for claim 20.
22. the method arbitrary according to claim 1 to 21 is characterized in that using ultrasound, and be at least softening until binding agent.
23. the method arbitrary according to claim 1 to 22 is characterized in that applied force on mixture, by carrying out pressing this mixture during the supersound process or after the supersound process.
24. according to the method for claim 23, it is characterized in that applying power during pressing mixture, the fracture strength that shows until this dosage form is 500N at least.
25. the method arbitrary according to claim 1 to 24 is characterized in that making mixture forming by pressing.
26. according to the method for claim 25, the molding that it is characterized in that mixture is at shaping mould and perforated auxiliary down by extruding and carrying out down the auxiliary of roller and/or chaser.
27. the method arbitrary according to claim 1 to 26 is characterized in that pressing and is to carry out down as perforated sound level auxiliary.
28. the method arbitrary according to claim 1 to 27 is characterized in that this mixture also comprises at least a following component a) to f):
(a) material of at least a stimulation nasal meatus and/or pharynx,
(b) at least a viscosifier, these viscosifier are liquid, aqueous by means of essential minimum, are preferably the aqueous extract that obtains from this dosage form, form a kind of gel, this gel preferably when joining volume more liquid, aqueous, still can be identified intuitively
(c) at least a antagonist with active component of abuse potential,
(d) at least a emetic,
(e) agent is detested at least a dyestuff conduct,
(f) at least a bitter substance.
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US10/890,703 US20050236741A1 (en) 2004-04-22 2004-07-14 Process for the production of an abuse-proofed solid dosage form
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